Oral cancer begins as a premalignant lesion in which a small nest of dysplastic cells expands while in contact with normal cells. During the recent grant period, unique models were developed which mimic the human mucosal and cutaneous microenvironment in premalignant disease and which showed that direct cell-to-cell contact between neighboring keratinocytes is crucial in controlling the development of invasive cancer from a premalignant lesion. It is known that loss of cell-cell contact mediated by intercellular adhesion is a central factor leading to the progression of advanced cancer and metastasis. However, the role of changes in intercellular adhesion in progression of early neoplasia in stratified epithelium is not clear. The objective of this application is to discover the intercellular pathways, which direct this, control it, or cause it to be lost. Because cadherins and catenins integrate cell adhesion with growth signaling they are excellent molecular candidates to regulate cell-cell interactions in premalignant disease. The experimental plan in this proposal is to perturb cadherins and catenins models of premalignancy and to monitor intraepithelial tumor cell expansion in vitro and invasion in vivo. The Principal Investigator hypothesizes that cadherin/catenin-mediated cell-cell interactions can control premalignancy and that changes in adhesions can activate pathways leading to cancer. He will test if overexpression of E-cadherin (Aim 1) or overexpression of alpha-catenin (Aim 2) will increase adherens junctions and limit neoplastic progression. The Principal Investigator will then determine if decreased adhesive interactions will trigger cancer progression by overexpressing dominant negative forms of E-cadherin (Aim 3) and desmosomal cadherins (Aim 4) to disrupt adherens junctions and desmosomes, respectively. He will test his hypotheses in tissue models, which mimic premalignant human stratified epithelium. Adenoviral vectors will be used to express these exogenous genes in short-term, in vitro studies and retroviral vectors will be used for long-term, in vivo studies using our novel human skin/nude mouse chimera. He expects to find cadherin-catenin-mediated pathways and mechanisms that will drive or arrest early neoplastic progression. This insight will be an important step towards finding new therapies to block premalignant disease progression and prevent cancer.